This invention relates to ligands of retinoid X receptor and pharmaceutical compositions for treating and/or preventing diseases which can be alleviated by the retinoid X receptor ligand (RXRL)-dependent transcriptional regulation of certain genetic information.
Diseases to be treated and/or prevented by use of the pharmaceutical compositions according to the present invention involve life-style related diseases. From the viewpoint of treating the life-style related diseases, there is an urgent need to develop drugs for use in the treatment of various vascular lesions causative of the onset of the life-style related diseases. Ischemic heart disease, which is prevalent when vascular lesions are present, is also referred to as coronary sclerosis. It is thought that around fifty percent of all deaths in the world are attributable this disease. Ischemic heart disease is the leading cause of death in most developed countries, and the second biggest cause of death in Japan. In addition it is estimated that the incidence of ischemic heart disease will rapidly increase in developing countries also. Major causes of ischemic heart disease, appear to include genetic factors, eating habits, stress, diabetes and hypertension. It is known that ischemic heart disease is closely related to life-style including diet. Hyperlipemia and hyperinsulinemia, which are induced by the excessive intake of high caloric diets, promote sedimentation of low density lipoproteins which are rich in cholesterol on the arterial wall. Degeneration of sedimented low density lipoproteins causes damage to the arterial wall; and leukocytes react to the damage in the arterial wall and infiltrate it to repair the lesion, resulting in chronic inflammation. Thus the mechanism of arteriosclerosis is understood to be as follows: In response to damage of arterial wall, leukocytes, which attempt to repair the damage, cause excessive inflammation which has the effect of thickening the arterial wall, resulting in a sclerosing lesion.
Typical examples of known drugs for preventing ischemic heart disease are hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors. These HMG-CoA reductase inhibitors, which inhibit the biosynthesis of mevalonic acid as a rate-determining step in the biosynthesis of cholesterol, reduce the amount of cholesterol synthesized in the liver and thus lower the cholesterol content in the low density lipoprotein which is synthesized in the liver and released into the serum. That is to say, the main function of these drugs resides in inhibiting the biosynthesis of cholesterol and lowering the cholesterol content in the serum, thereby reducing the low density lipoprotein incorporated from the serum into the arterial wall depending on the concentration. Namely, these drugs exert a merely indirect and preventive effect. These HMG-CoA reductase inhibitors exhibit no effect on the sclerosing lesions associated with chronic inflammation which thickens the arterial wall in which macrophages and lymphocytes participate. Thus, it is impossible to achieve any direct therapeutic effect for healing chronic inflammation of an artery. An ideal remedy and/or preventive treatment for arteriosclerosis is a drug which shows an effect of lowering serum cholesterol level and, at the same time, a therapeutic and/or preventive effect on chronic inflammation induced by the sedimentation of cholesterol on the arterial wall. It is expected that such a drug, if any, would serve as an ideal remedy and/or preventive treatment for ischemic heart disease.
Similar to the coronary artery, the cerebral artery frequently suffers from lesions. When a cerebrovascular lesion proceeds, cerebrovascular lesions such as intracerebral bleeding or cerebral infarction are induced. Once a cerebrovascular lesion has occurred, there frequently result serious consequences such as movement disorder or intellectual disorder, even though death may be avoided. In a society where the population is aging, an increase in bedridden persons or persons suffering from senile dementia gives rise to serious social problems, and thus there is an urgent need to prevent these problems from the viewpoint of relieving the social burden of medical expenses, also. In Japan, the number of persons suffering from dementia caused by cerebrovascular dementia (i.e., partial degeneration and/or necrosis of the brain due to cerebrovascular lesions) amounts to almost 50% of the total number of persons suffering from dementia. Different from the coronary artery, the surface of the cerebral artery is coated with endothelial cells which closely overlap each other on the contact face. This coated state is referred to as tight junction. In the endothelium of the cerebral artery, endothelial cells are arranged closely without any voids. Therefore, low density lipoprotein is not incorporated into the arterial wall as in the heart. In other words, cholesterol will not induce arteriosclerosis in the cerebral artery. However, when the artery becomes enlarged due to hypertension and damage to the cerebral artery is caused, plasma components are able to penetrate the arterial wall. In response to such damage, leukocytes infiltrate the arterial wall, and as in the case of the coronary artery in the heart, the repair reaction becomes excessive. As a result, the cerebral arterial wall thickens whereby blood circulation disorders are caused; or the arterial wall becomes fragile as a result of chronic inflammation and fails to withstand blood pressure, whereby an aneurysm forms. When an aneurysm breaks, bleeding results, i.e., cerebral stroke. Thus, cerebrovascular lesion can be seen to result from chronic inflammation induced by the infiltration of leukocytes responding to repair small wounds in the artery, similar to coronary arteriosclerosis.
To prevent cerebrovascular lesions, hypotensive drugs have been employed exclusively. The effect of these hypotensive drugs resides in a lowering of blood pressure to protect vessels from excessive pressure, thereby preventing vascular damage. In other words, hypotensive drugs are employed as a preventative treatment to avoid negative effects consequent to (natural) repair of cerebral vessels. In Japan, there is a category of remedies for cerebrovascular dementia which are referred to as cerebral vasodilators, and it has been a practice to employ cerebral vasodilators such as idebenone, bifemelane hydrochloride, indeloxazine hydrochloride, nicergoline and propentofylline. As a result of clinical re-evaluation tests, however, it has been clarified that these drugs show no significant difference from placebos in therapeutic effect on negative consequences of cerebrovascular lesions. Accordingly, these drugs are no longer indicated for the treatment of the negative consequences of cerebrovascular lesions. Thus, it may be concluded that no remedy exists for the negative consequences of cerebrovascular lesions at the present time. It is expected that a drug having a hypotensive effect as well as a therapeutic effect on chronic inflammation of the cerebral artery, if any are present, would serve as an ideal remedy for cerebrovascular lesions.
As discussed above, it has been revealed that vascular lesions such as arteriosclerosis and aneurysm are induced by the repair of damage to the artery. It is known that arteriosclerosis is caused by damage to the arterial wall in a case where a narrowed artery is enlarged by inserting a balloon or a stent into it, or T lymphocytes of a host undergo a rejection reaction against an isoantigen which is present in the artery of a transplanted organ; in addition to chemical stimulus by, for example, a harmful degenerated agent such as degenerated low density lipoproteins, or under the physical stimulus of hypertension.
As examples of physical factors causative of arteriosclerosis, a treatment of inserting a balloon or a stent into a narrowed part of a coronary artery to enlarge a narrowed section (i.e., percutaneous angioplasty) may be cited. Due to its convenience and immediate effect, this treatment for enlarging physically a narrowed inner cavity of a coronary artery has been carried out at a frequency of 1,000,000 cases per year across the world since 1996. Since the inner cavity of a narrowed part of the artery is enlarged immediately by applying a physical force, the artery is damaged, with the result that leukocytes responsive to such damage infiltrate the area in an excessive repair reaction. It is known that thickening of the arterial wall at the enlarged part arises within 6 months in about 40% of patients in the case of enlargement with a balloon catheter, while re-constriction arises within 6 months in 20 to 40% of patients in the case of enlargement with a stent. In the case where re-constriction arises, it becomes necessary to perform percutaneous angioplasty once more or to perform coronary artery bypass to save life. That is to say, although percutaneous angioplasty is highly effective in rapidly enlarging an intraarterial cavity, no adequate means of preventing arteriosclerosis resulting from vascular damage due to enlargement of the intraarterial cavity has been found so far.
Arteriosclerosis caused by an immunological mechanism is typified by arteriosclerosis associated with organ transplantation. Relatively recently, T lymphocyte-specific immunosuppressants such as cyclosporin and tacrolimus have been developed, and thus acute rejections of transplanted organs within a year of transplantation can be suppressed almost completely. In heart, liver, kidney or cardiopulmonary transplantation, however, over 5 years in around 60% of cases transplanted organs remain accepted. Conversely, in about 40% of cases a phenomenon referred to as chronic rejection occurs. This phenomenon can be discriminated from acute rejection which occurs within one year following transplantation. Although the name xe2x80x9cchronic rejectionxe2x80x9d is indicative that a transplanted organ has been rejected immunologically, it actually describes a condition where necrosis and drop-off of the transplanted organ occur as a result of circulatory disorders caused by arteriosclerosis. Chronic rejection is induced by damage which occurs as a result of immunological attack following recognition of an isoantigen in the artery of the transplanted organ by lymphocytes of the host. Then, leukocytes of the host in response to damage caused by the immunological attack react to repair the damage, thereby inducing arteriosclerosis. It has been clarified that chronic rejection correlates to the strength of an initial acute rejection. Namely, if an acute rejection is strong, the subsequent risk of the transplanted organ being lost within 5 years becomes high, as result of the artery of the transplanted organ being subject to more serious immunological damage. The reason is that arteriosclerosis is likely induced by an excessive repair reaction. If a means of regulating excessive chronic inflammation in an artery can be developed, chronic rejection can be halved in the case of organ transplantation. Thus, the background of the occurrence of arteriosclerosis has been illustrated.
The pharmaceutical compositions according to the present invention are aimed at treating type I diabetes and type II diabetes which are typical metabolic diseases. Type II diabetes is a life-style related disease, and closely correlates to obesity which, in turn, is dependent on both eating habits and genetic factors. In contrast, type I diabetes is a disease which arises when there is a lack in the overall amount of available insulin, which occurs when insulin-producing xcex2 cells are destroyed by an autoimmune reaction against pancreatic Langerhans"" islet xcex2-cells. Thus, administration of regular insulin injections is required to ensure the survival of patients with this disease. Although these diseases outlined above differ from each other in terms of cause, the complications of diabetes, which arise when the disease has been present for a long period of time, are common to both types. Diet therapy and exercise therapy are the major ways in which type II diabetes caused by the peripheral insulin resistance is treated, and drug therapy is employed merely an adjunct. In drug therapy, use is made of sufonylurea agents which accelerate insulin secretion from the pancreatic Langerhans"" islet, and biguanide agents which promoting glucose utilization in peripheral tissue. However, there has been available no drug which is capable of activating peripheral insulin resistance which is causative of the onset of the disease. Thiazolidinedionediene (TZD) compounds developed recently have attracted attention as drugs having the ability to activate peripheral insulin resistance.
Several ten receptors referred to collectively as a nuclear receptor superfamily, which are known as receptors of fat-soluble hormones and vitamins, have been found in nuclei. In the course of studying the function of mechanism of synthetic organic TZD compounds, facts have been determined as follow: (1) the target tissue of these compounds are adipocyte tissue; (2) they are agonists specifically activating PPARxcex1, a member of the nuclear receptor superfamily; and (3) they differentiate certain fibroblasts having been conditioned into adipocytes, at the cell culture level. After being activated by TZD, PPARxcex3 forms a dimer (heterodimer) together with retinoid X receptor (RXR), which is also a nuclear receptor, and binds to a specific site (hormone recognition site) of chromosome thereby regulate the transcription of a definite gene. Based on experiments at the cell and tissue levels, it has been proved that the transcriptional regulation by this heterodimer contributes to the enhancement of the peripheral insulin sensitivity. That is to say, TZD activates PPARxcex3 in adipocyte tissue dose-dependently and thus ameliorates the metabolic disorder in diabetes. Since there has been known no drug which acts on a gene and regulates the expression of a gene signal, it is it is to be expected that TZD would be so highly evaluated.
Since various ligands (for example, fatty acids, prostaglandins, nonsteroidal analgesic/anti-inflammatory agents) bind to the PPARxcex3 receptor, the specificity of TZD to the PPARxcex3 receptor is not necessarily high. Since the existing TZD compounds have a characteristic function of activating PPARxcex1 also and thus proliferating mammalian hapatocellular peroxisome thereby causing hepatic hypertrophy, it is doubted that these TZD compounds might relate to hepatopathy. Among them, troglitazone, which have been put into practical use for the first time among TZD compounds, causes hepatopathy in about 2% of patients at the normal dose and can cause death in extreme cases. Therefore, much attention needs to be paid in using such compounds from the viewpoint of safety. Provided that PPARxcex3 agonists activate widely peripheral insulin resistance, these agonists must be considered useful not only in ameliorating metabolic disorder in diabetes but also in treating and/or preventing the complications of diabetes. However, on the basis of the results of animal experiments and clinical data on the TZD compounds, it cannot be concluded that the symptoms of insulin resistance syndrome and the complications of diabetes can be ameliorated significantly. Therefore, it there remains scope for improvement of TZD compounds, taking into consideration specificity of function, safety and usefulness.
On the other hand, it attention has drawn to what effect the RXR ligand forming a heterodimer together with PPARxcex3 exerts on the metabolic disorder of type II diabetes. This is because PPARxcex3 forms a heterodimer together with RXR and thus regulates the expression of the gene signal involved in the onset of diabetes. A first study suggesting a new direction for this problem was reported by researchers of Ligand, USA (Nature 386:407-410, 1997). According to thier report, retinoid derivatives LG100268 and LGD1069, which were under development as remedies for promyelocystic leukemia and Kaposi""s sarcoma, showed effects in cell culture and animal experiments as follow: (1) these derivatives form heterodimers with PPARxcex3 as an RXR ligand and thus regulate gene transcription; (2) and when orally administered to hereditary obese diabetic mice ob/ob and db/db, they enhance the insulin sensitivity and drastically lower blood glucose levels, serum neutral fat levels and serum insulin levels. The researchers further reported that a significant effect of ameliorating metabolism could be achieved by the combined administration of a retinoid derivative with a TZD compound, each in such a small dose as to show no drug effect alone, and thus indicated that the ligand of RXR and the ligand of PPARxcex3 would exhibit a synergistic effect in vivo.
The retinoid derivatives reported by the researchers were synthesized in order to potentiate the effect of all-trans retinoic acid (ATRA) and alleviate side effects. It is said that these derivatives are effective against skin cancers such as Kaposi""s sarcoma and promyelocystic leukemia. Namely, these derivatives also bind to ATRA receptor (RAR) and exert a retinoid activity and, therefore, are poor in specificity of function. In addition, these retinoid derivatives have marked toxicity inherent to ATRA, which makes them unusable as a life-long remedy for diabetes. An RXR-specific ligand, which is free of these problems, has high safety and exerts a considerable effect of potentiating insulin sensitivity, would be a drug showing great promise as a remedy for diabetes and its complications.
It is known that PPARxcex3 receptor is expressed in a large amount not only in adipocyte tissue, which is the target of the treatment for II type diabetes, but also in the spleen, intestinal tract and adrenal gland. Thus, studies are now in progress to determine the roles of PPARxcex3 expressed in these organs. Among them, two noteworthy reports on the role of PPARxcex3 expressed in lymphoid cells have been published recently (M. Ricote et al., The peroxisome proliferator-activated receptor-g is a negative regulator of macrophage activation. Nature 391:79-82, 1998; and C. Jiang, A. T. Tiang and B. Seed. PPARxcex3 agonists inhibit production of monocyte inflammatory cytokines. Nature 391:82-86, 1998). These studies are focused on PPARxcex3 expressed in activated macrophages triggering the induction of chronic inflammation. When macrophages infiltrate an inflammatory site and undergo activation, inflammatory cytokines are synthesized vigorously. However, the transcription of genes relating to such chronic inflammation can be suppressed dose-dependently by adding a nonsteroidal analgesic/anti-inflammatory agent, which is a ligand of PPARxcex3, to the culture of activated macrophages. It has also been clarified that the ligand of PPARxcex3 competes partially with the transcriptional promotion factors AP-1, STAT and NF-kB, and thus regulates the expression of inflammatory cytokine genes. That is to say, ligands of PPARxcex3 such as nonsteroidal analgesic/anti-inflammatory agents reduce the production of the inflammatory cytokine messenger RNA (IL-1xcex2, TNFxcex1, IL-6, etc.) having been vigorously transcribed in association with the activation of macrophages and, in turn, regulate the production of these inflammatory cytokines. Unfortunately, the existing TZD compounds acting mainly on adipocytes scarcely regulate the production of inflammatory cytokines by activated macrophages. Accordingly, it is impossible at the present stage to treat chronic inflammation with the use of these TZD compounds. However, it has been suggested that regulation of inflammatory cytokines by the ligand of PPARxcex3 may contribute to the treatment of chronic inflammation such as arteriosclerosis, complications of diabetes and rheumatoid arthritis. However, no study has been made so far concerning ligands of RXR which might be capable of forming a heterodimer together with PPARxcex3, and thereby regulate the expression of a gene signal relating to the onset of chronic inflammation.
It is considered that the function of mechanism of nonsteroidal analgesic/anti-inflammatory agents resides in the suppression of the production of prostaglandins which causes pain and swelling at the inflammation site. However, the authors of the above-described reports suggest that the suppression of the transcription of genes encoding inflammatory cytokines also relate to the function of mechanism as well as the suppression of the biosynthesis of prostaglandins. It is well known that nonsteroidal analgesic/anti-inflammatory agents are effective against rheumatoid arthritis. Sugar corticoids, which are frequently used in treating chronic inflammation similar to nonsteroidal analgesic/anti-inflammatory agents, exert a therapeutic and/or preventive effect on rat adjuvant arthritis which is an experimental model of arteriosclerosis and rheumatoid arthritis. However, these drugs can not be administered over a long time continuously, since they suppress the biosynthesis of prostaglandins in the digestive tract mucosa resulting in a high incidence of digestive ulcers. The suppression of the production of inflammatory cytokines by activated macrophages accumulated at the inflammation site by a ligand of PPARxcex3 not suppressing the prostaglandin biosynthesis, if possible, would, without doubt, make a substantial contribution to the treatment of chronic inflammatory conditions such as arteriosclerosis, complications of diabetes and rheumatoid arthritis. However, at the present stage, such an assumption remains hypothetical, and thus its usefulness needs to be confirmed experimentally and clinically. The TZD compounds, which are synthesized as ligands of PPARxcex3, exhibit only a weak effect in suppressing the production of inflammatory cytokines, and thus have little practical use. Although TZD strongly acts on PPARxcex3 in white adipose tissue, it shows only a weak effect on activated macrophages. Therefore, it seems that existing TZD compounds are hardly capable of suppressing the production of inflammatory cytokines. Moreover, it is completely unknown what effects ligands of RXR forming a heterodimer with PPARxcex3 exert on activated macrophages. It is also unclear whether or not PPARxcex3 forms a heterodimer with RXR in macrophages, as in adipocyte tissue, and specifically regulates gene transcription. As discussed above, it is known that nonsteroidal analgesic/anti-inflammatory agents serve as ligands of PPARxcex3 and suppress the production of cytokines causative of chronic inflammation at the cell culture level. Thus, the effects of RXR ligands on the production of inflammatory cytokines have also attracted public attention. It is projected that intensive studies will be carried out focusing on ligands of PPARxcex3 and RXR as anti-inflammatory agents against chronic inflammation.
To treat chronic inflammation such as rheumatoid arthritis and autoimmune diseases, it has been a practice to employ nonsteroidal analgesic/anti-inflammatory agents or sugar corticoids which are employed generally in treating acute inflammation. Namely, it can be said that to date there has been no remedy specific for chronic inflammation. Nonsteroidal analgesic/anti-inflammatory agents suffer from a problem that their prolonged use frequently induces has undesirable side effects on the digestive system such as ulcers, since these drugs suppress the biosynthesis of prostaglandins. On the other hand, sugar corticoids have a number of side effects including frequent onset of infectious diseases due to immune suppression, induction of metabolic disorders such as diabetes, and a rebound phenomenon, i.e., whereby discontinuation of administration of the drug brings about a worsening of a treated condition as compared to the state prior to commencement of drug administration. Thus, it can not be said that the quality of life (QOL) of patients is remarkably improved by existing therapies for chronic inflammation. In addition to these problems of drug therapy, attention has to be paid to complications of diabetes occurring due to inflammation in microvessels. Since complications of diabetes fall within the category of chronic inflammation, there is a high possibility that such complications can be prevented and/or treated by administering a drug which exerts an effect of specifically ameliorating chronic inflammation. To treat chronic inflammatory conditions such as rheumatoid arthritis, arteriosclerosis, diabetic microangiopathy, periarteritis nodosa and aneurysm, it is necessary to develop a drug capable of treating chronic inflammation without any worsening of QOL as a result of the frequent occurrence of undesirable side effects.
In postmenopausal females, calcium metabolic disorders arise frequently and osteoporosis is a serious problem in this population group. Osteoporosis is characterized morphologically by a reduction in trabecula, enlargement of Harbor tube, and enlargement of medullary cavity with thinned cortical bone without any morphological change of bone. These pathogenic conditions relate to disorders in the relation between bone resorption and bone addition. Osteopolyporosis observed in postmenopausal females is a typical example. Once suffering from osteoporosis, patients are liable to suffer bone fractures even as a result of slight stresses due to a marked decrease in bone strength. Methods for treating osteoporosis include oral administration of female hormone, activated vitamin D3 or biphosphite drugs and injection of calcitonin. A preferable treatment, for preventing and/or treating osteoporosis would be to potentiate the efficacy of endogenous activated vitamin D3. However, no study has until now been initiated from this viewpoint, due to a lack of possible approaches.
The present invention has been made based on a novel finding that ascochlorin and its homologues (each having a structure with a terpenoid side chain (preferably carrying about 20 carbon atoms) attached to the 3-position of orcylaldehyde), which have been previously reported by the inventors as fat-soluble antibiotics produced by fungi, are ligands of retinoid X receptor. In particular, the present invention depends on an unexpected finding that, because of having an aldehyde group, ascochlorin and its homologues react with the amino group of serum protein and form Schiff bases in vitro, thereby showing no side effects of retinoids.
Ascochlorin and its homologues are ligands of retinoid X receptor and usable in treating and/or preventing diseases or conditions which can be alleviated by the retinoid X receptor ligand-dependent gene signal transcriptional regulation (for example, diseases caused by the expression of insulin resistance, hypertension, cerebral angiopathy, rheumatoid arthritis, autoimmune diseases, calcium metabolic disorder, complication of diabetes, arterial restenosis following percuneous transluminal coronoary angioplasty, arteriosclerosis following organ transplantation). Also, these compounds inhibit degeneration and/or necrosis of pancreatic Langerhans"" islet xcex2-cells and are usable to make these cells to sustain the insulin productivity. Accordingly, the present invention provides pharmaceutical compositions containing these compounds, a therapeutic and/or preventive method with the use of these compounds, and use of these compounds for treating and/or preventing the diseases above.